Elsevier

Biological Psychiatry

Volume 78, Issue 5, 1 September 2015, Pages E15-E27
Biological Psychiatry

Review
An Overview of Translationally Informed Treatments for Posttraumatic Stress Disorder: Animal Models of Pavlovian Fear Conditioning to Human Clinical Trials

https://doi.org/10.1016/j.biopsych.2015.06.008Get rights and content

Abstract

Posttraumatic stress disorder manifests after exposure to a traumatic event and is characterized by avoidance/numbing, intrusive symptoms and flashbacks, mood and cognitive disruptions, and hyperarousal/reactivity symptoms. These symptoms reflect dysregulation of the fear system likely caused by poor fear inhibition/extinction, increased generalization, and/or enhanced consolidation or acquisition of fear. These phenotypes can be modeled in animal subjects using Pavlovian fear conditioning, allowing investigation of the underlying neurobiology of normative and pathological fear. Preclinical studies reveal a number of neurotransmitter systems and circuits critical for aversive learning and memory that have informed the development of therapies used in human clinical trials. In this review, we discuss the evidence for a number of established and emerging pharmacotherapies and device-based treatments for posttraumatic stress disorder that have been developed via a bench to bedside translational model.

Section snippets

Pharmacotherapy Approaches to Fear- and Anxiety-Related Disorders

The following sections review preclinical and clinical evidence for a variety of established and emerging pharmacotherapies, especially focusing on underlying transmitter and receptor systems, as well as targeted brain regions. In discussing the preclinical data, we focus on outlining evidence from studies of cued and contextual fear conditioning but include discussion of evidence from alternative fear and anxiety paradigms where relevant.

Device-Based Treatments

Increasingly, researchers are investigating device-based treatments to alter pathological brain activity and connectivity in psychiatric disease. A number of different stimulation tools—including DBS, vagus nerve stimulation, transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS)—are under investigation and each are at various stages of development and testing at the preclinical and clinical levels (222, 223). Similar to traditional pharmaceutical drugs,

Discussion

We have examined the evidence regarding efficacy of some specific treatment strategies for PTSD informed by rodent preclinical studies. We have focused on Pavlovian fear conditioning and extinction experiments in animals, which allow researchers to model aversive learning processes that may underlie development of PTSD in response to trauma, as well as extinction of pathological fear via exposure therapy. Even in prior stress models, which are thought to more thoroughly model PTSD, fear

Acknowledgments and Disclosures

Support was provided by National Institutes of Health (T32-GM08605, 1F31MH097397, and R01MH096764), the Burroughs Wellcome Fund, and by an National Institutes of Health/National Center for Research Resources base grant (P51RR000165) to Yerkes National Primate Research Center.

Dr. Ressler is a founding member of Extinction Pharmaceuticals/Therapade Technologies to develop D-cycloserine, a generically available compound, for use to augment the effectiveness of psychotherapy. He has received no

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